Significance The immune system strikes a careful balance between launching a robust response to threats and avoiding overactivation. The molecule cGAMP is an immunotransmitter that activates innate immunity and signals extracellularly, where it is subject to degradation by the enzyme ENPP1. Here, we engineer ENPP1 to lose activity toward cGAMP but not other substrates, thus creating a biochemically precise tool to understand how ENPP1 regulates extracellular cGAMP and thus innate immunity. We uncover that ENPP1's degradation of extracellular cGAMP has a long evolutionary history, and that this mechanism is critical for controlling diverse immune threats, including viral infection and inflammation.

The innate immune system is an organism’s first line of defense against an onslaught of internal and external threats. The downstream adaptive immune system has been a popular target for therapeutic intervention, while there is a relative paucity of therapeutics targeting the innate immune system. However, the innate immune system plays a critical role in many human diseases, such as microbial infection, cancer, and autoimmunity, highlighting the need for ongoing therapeutic research. In this review, we discuss the major innate immune pathways and detail the molecular strategies underpinning successful therapeutics targeting each pathway as well as previous and ongoing efforts. We will also discuss any recent discoveries that could inform the development of novel therapeutic strategies. As our understanding of the innate immune system continues to develop, we envision that therapies harnessing the power of the innate immune system will become the mainstay of treatment for a wide variety of human diseases.

Silver nanoparticles (AgNPs) are widely sought after for a variety of biomedical and environmental applications due to their antimicrobial and catalytic properties. We present here a green and simple synthesis of AgNPs utilizing traditional Chinese medicinal herbs. The screening of 20 aqueous herb extracts shows that Sheng Di Huang (Rehmannia glutinosa) had the most promising potential in producing AgNPs of 30±6 nm, with narrow size distribution and high crystallinity. The antimicrobial activities of these AgNPs conducted on E. coli cells were found to be superior in comparison to poly(vinylpyrrolidone)‐capped AgNPs synthesized using common chemical method. Additionally, the AgNPs obtained possess excellent catalytic performance in the reduction of 4‐nitrophenol to 4‐aminophenol. We compared the phytochemical and FTIR spectral analyses of the herb extract before and after synthesis, in order to elucidate the phytochemicals responsible for the reduction of Ag+ ions and the capping of the AgNPs produced.

Autoimmune disorders are frequently exacerbated by aberrant STING signaling. While STING inhibitors are highly sought after, no viable therapeutic strategies have been reported. When stimulated, STING undergoes a multi-step mechanism to activate downstream interferon-stimulated genes (ISGs), including palmitoylation, translocation from the ER to the Golgi, and oligomerization, but it remains unclear which step(s) are strictly required and therefore should be targeted by potential STING inhibitors. Here, we comprehensively established the order and determined the necessity of each STING activation step. We find that ER-to-Golgi translocation is dispensable for downstream ISG activation, and a previously studied palmitoylation site, C91, is not required for activation in all contexts. Cysteine reactivity mapping and metabolic labeling identified a new palmitoylation site, C64, that is basally palmitoylated and required for STING activation, but is not druggable due to poor solvent accessibility. We confirm that the oligomerization step of STING activation is strictly required, and therefore developed a short peptide mimicking its natural autoinhibitory domain that effectively inhibits STING activation: a proof of concept for the first viable strategy for developing STING inhibitors.

Escherichia coli and other Enterobacteriaceae thrive in robust biofilm communities through the coproduction of curli amyloid fibers and phosphoethanolamine cellulose. Curli promote adhesion to abiotic surfaces and plant and human host tissues and are associated with pathogenesis in urinary tract infection and food‐borne illness. The production of curli in the host has also been implicated in the pathogenesis of neurodegenerative diseases. We report that the natural product nordihydroguaiaretic acid (NDGA) is effective as a curlicide in E. coli. NDGA prevents CsgA polymerization in vitro in a dose‐dependent manner. NDGA selectively inhibits cell‐associated curli assembly and inhibits uropathogenic E. coli biofilm formation. More broadly, this work emphasizes the ability to evaluate and identify bioactive amyloid assembly inhibitors by using the powerful gene‐directed amyloid biogenesis machinery in E. coli.